Relapse after orthodontic tooth movement is a significant problem in orthodontics. The purpose of this study was to examine the efficacy of the osteoclast inhibitor osteoprotegerin-Fc (OPG-Fc) for inhibiting postorthodontic relapse. Rat maxillary molars were moved mesially and allowed to relapse for 24 days. Low-dose (1 mg/kg) or high-dose (5 mg/kg) OPG-Fc or saline was injected adjacent to the molars during relapse. Tooth movement, micro-CT, histologic bone quality, and serum OPG and TRAP-5b were measured. OPG-Fc injections significantly diminished postorthodontic relapse from 63% (0.78/1.20 mm) of total movement in vehicle control rats to 31% (0.31/1.00 mm) in low-dose and 24% (0.28/1.16 mm) in high-dose OPG-Fc groups 24 days after appliance removal. Normalization of bone and periodontal tissues occurred as early as 8 and 16 days in the high- and low-dose OPG-Fc-treated groups, respectively, while the vehicle-treated group showed only partial tissue recovery 24 days following tooth movement. After 24 days of relapse, there was complete recovery to pre-tooth-movement values for bone volume fraction (BVF) and tissue mineral density (TMD) in both the low- and high-dose OPG-Fc groups, while BVF recovered only partially and TMD did not recover in the vehicle control group. Greatly elevated serum OPG levels and reduced serum TRAP-5b levels in OPG-Fc-treated animals indicated systemic exposure to locally injected drug. The profound decrease in postorthodontic relapse by local OPG-Fc administration indicates that osteoclasts are critical to bone maturation following tooth movement and points to the potential pharmacologic use of OPG-Fc or other RANKL inhibitors for orthodontic retention.